Transdermal therapeutic systems (TTS) have been known for a number of years among those skilled in the art and have been launched on the market. Transdermal therapeutic systems are self-adhesive pharmaceutical preparations which are to be applied to the skin, have a fixed application area, and deliver a medicinal substance to the human or animal body in a manner controlled according to time and quantity.
The therapeutic advance of these systems by comparison with traditional administration forms is that the active ingredient is supplied to the body not intermittently, as for example on intake of tablets, but continuously.
This results on the one hand in extending the duration of action of a medicinal substance, and on the other hand substantially preventing side effects through avoiding unnecessary peaks in the blood level.
The forms normally employed for such systems are layered, flat and use various polymers, of which polyethylene terephthalate, polyisobutylene, polysiloxane are mentioned by way of example.
For the purpose of improving the adhesion to moist surfaces it is possible to introduce, besides numerous substances known to the skilled person (resins, oils, fillers, stabilizers), also water-soluble/swellable additions (EP 0307187). Nanoparticulate excipients have also been employed experimentally as excipients for transdermal delivery (J. Microencaps. (1991), p. 369-374), although with limited success. Besides the more customary polymeric excipients, experiments have also been carried out with nanostructured lipid carriers for active ingredients, e.g. with indomethacin (J. Pharm. Sei. (2005), p. 1149-1159).
The opinion prevailing among experts in the early days of transdermal systems was that the main difficulty of delivery through the skin was the need to control the rate of delivery. For this reason, membranes controlling the active ingredient and, inter alia, also the optional absorption enhancer were introduced into such systems (here for example U.S. Pat. No. 4,460,372). Attempts were also made to regulate the control of delivery in this way by particle sizes of varying dimensions extending to micro- and nanoparticles (U.S. Pat. No. 4,687,481).
Since the human skin does not, however, have a permeability sufficient for all medicinal substances under consideration, only a small number of active ingredients can be employed in transdermal therapeutic systems of the conventional type. Numerous attempts have therefore been made with the aim of increasing the natural permeability of skin.
One such possibility is to use so-called penetration enhancers or absorption promoters. By these are meant substances which achieve a marked increase in the active ingredient flux by chemical/physical interaction with the microstructure of the skin. However, many of these substances have a toxic effect on the skin or cause irritation. Nor is the onset of the effect of these absorption promoters always sufficiently fast, so that the effect is difficult to control.
Another possibility is the use of physical principles such as, for example, of ionophoresis, of ultrasound-assisted permeation enhancement (sonophoresis) or else the use of microneedles (e.g. U.S. Pat. No. 3,964,482). However, these methods require comparatively elaborate additional devices in the transdermal therapeutic system, which ordinarily make this type of therapy uneconomical.
A fundamentally different way of increasing the permeability of skin is to increase the thermodynamic activity of the active ingredient. Attempts to this aim at increasing the active ingredient concentration acting from the outside in order to increase the permeation. These efforts were limited by the fact that it is not generally possible to increase the concentration of an active ingredient above the saturation solubility. On the other hand, the use of formulation bases with greater solubility for the active ingredient in the transdermal therapeutic system is no help because, in such cases, the link between the partition coefficient and solubility according to Nernst's partition law comes into operation and has a limiting effect.
It is possible for so-called supersaturated states to arise temporarily, where the dissolved active ingredient concentration is above the saturation concentration, e.g. when a saturated solution is cooled. Such systems are described for example in U.S. Pat. No. 5,174,995, in which saturated solutions of active ingredients are placed on the skin and lead, through the influence of the de-solubilizing effect of the moisture on the skin, to supersaturation and thus increased transport of active ingredient. It is obvious that utilization of such states in liquids rapidly fails through precipitation of the active substance and accordingly reduced concentrations and delivery rates. Supersaturated states can be generated and maintained longer in transdermally customary adhesive polymers than in solutions of liquid media (J. Pharm. Sci. (2004), p. 2039-2048). A concentration of up to four times the saturation solubility was successfully maintained for minutes to days here. However, even this stability is far from sufficient for marketable transdermal systems. With certain active ingredients whose melting point is not much above room temperature, such as, for example, scopolamine, such supersaturations can, however, be stabilized in some circumstances for a sufficiently long time through technical production measures (U.S. Pat. No. 6,238,700).
A stable system cannot be achieved with this proposed solution for active ingredients which are in particulate form and whose melting point is distinctly above room temperature (thus above about 50° C.). It is, however, possible to achieve a storable system by combining a layer which limits the access of moisture from the skin, and a matrix with water-insoluble base material and, present therein, inclusions which in turn comprise the active ingredient as disclosed in DE 39 10 543, which system enters a supersaturated state only on exposure to moisture from the skin and thus brings about the desired increased active ingredient flux only on use,
Unfortunately, the solution to the problem according to the present state of the art is still associated with disadvantages. Thus, the solution proposed in DE 39 10 543 requires the active ingredient to be incorporated in dissolved (solid-dissolved) form. This is associated with the risk of premature inactivation of sensitive active ingredients through chemical degradation, since active ingredients are less stable in solution than in solid crystalline form (U.S. Pat. No. 5,716,636), It is moreover difficult to adjust the extent and the time course of the supersaturation, because they depend greatly on the degree of swelling of the inclusions (islands) in connection with the obligatory layer which limits the access of moisture. A further disadvantage of this prior art is, again because of the requirement to provide a dissolved inner phase of the active ingredient, the need to employ a comparatively large amount of excipient for the base material of the islands, because otherwise slightly soluble medicinal substances cannot be converted into a solid solution. This makes it difficult or impossible to design flexible and thin patches which are preferred by consumers and patients.